Tumors are one of main diseases that seriously threaten the lives and quality of life of human beings. According to statistical data of the World Health Organization (WHO), patients that die of tumors are about 6.9 millions per year in the world. Since living environment and living habit vary, the morbidity rate and mortality rate of tumors has increased gradually in recent years due to unhealthy environment and some disadvantageous factors.
The traditional treatment regimes for tumors are performed by discovering and destroying tumors. At present, owing to the further research of cell signal transduction pathways and deep knowledge of actions of oncogenes and antioncogenes in tumor cells, the development of antitumor drugs that are directed against cancer-specific molecule targets attracts more attention and becomes a research focus in the art. As a new treatment regime targeted therapy of tumors has been clinically applied, and has got remarkable progress in recent years. It is known that signal pathway of protein tyrosine kinases (PTK) is closely related to the proliferation, differentiation, migration and apoptosis of tumor cells (cf. Li Sun, et al., Drug Discov Today, 2000, 5, 344-353), and a protein tyrosine kinase inhibitor can be used to interfere or block tyrosine kinase pathways to treat tumors (cf. Fabbro D., et al., Curr Opin Pharmacol, 2002, 2, 374-381).
Protein tyrosine kinases (PTK) are members of oncoprotein and proto-oncoprotein families that are important in the normal and abnormal cell proliferation, and are enzymes that can selectively phosphorylate tyrosine residues of different substrates, catalyze the transfer of the γ-phosphate group from adenosine triphosphate to tyrosine residues of many important proteins, and phosphorylate phenolic hydroxyl. Protein tyrosine kinases include receptor tyrosine kinases (RTK), non-receptor tyrosine kinases, and IR and Janus kinases etc. (cf. Robinson D. R., et al., Oncogene, 2000, 19, 5548-5557), wherein most of them are receptor tyrosine kinases (RTK). Receptor tyrosine kinases (RTK) are endogenous protein tyrosine kinases, take part in the regulation of a number of cells, play an important role in the transmission of mitogenic signals which initiate cell replication, and regulate the cell growth and differentiation. All RTKs belong to type I membrane-spanning cell surface proteins having a similar topological structure, i.e., they have a large glycosylated extraceullular ligand binding domain, a hydrophobic transmembrane domain, and an intracellular tyrosine kinase catalytic domain as well as a regulation sequence. It is known that ligand binding (for example, the binding of an epidermal growth factor (EGF) or of an EGFR) results in activation of activity of partially encoded receptor kinase in the receptor, thereby phosphorylating critical tyrosine amino acids to lead to transduction of proliferative signal across cell membrane.
The receptor tyrosine kinases can be divided into 4 different sub-groups based on the different structures of subunits in the extraceullular ligand binding domain (cf. Ullrich A. et al., Cell, 1990, 61, 203-212): the first sub-group (i.e., erbB family) comprises epidermal growth factor receptor (EGFR), HER2/Neu, HER3/c-erbB3, and the like; the second sub-group comprises insulin receptors, insulin-like growth factor-1 (IGF-1) receptors, and the like; the third sub-group comprises PDGFR-α, PDGFR-β, colony-stimulating actor-1 receptors (CSF-IR), c-Kit, and the like; and the further sub-group comprises FGFR-1, FGFR-2, FGFR-3, FGFR-4, and the like, wherein the third and fourth sub-groupes contain 5 and 3 extracellular immunoglobulin-like domains, respectively. After binding to a corresponding ligand, RTK can initiate the formation of a homodimer or heterodimer in receptors, activate PTK, and catalyze the transfer of the phosphate group from adenosine triphosphate to tyrosine residues of receptors to phosphorylate the tyrosine residues. The autophosphorylation of receptors produces two effects, that is, activation of inherent catalytic activity and formation of binding sites of effect proteins, to thereby activate downstream signal molecules (cf. Zhu Xiaofeng et al, Acta Pharmaceutica Sinica, 2002, 37, 229-234; Deng Xiaoqiang et al, Acta Pharmaceutica Sinica, 2007, 42, 1232-1236).
Main signal transduction pathways of the receptor tyrosine kinases include Ras (retrovirus-associated DNA sequences)/Raf (rapidly accelerated fibrosarcoma)/MAPK (mitogen activated protein kinase) pathways and PI-3K (phosphatidylinositol-3 kinase)/Akt (protein kinase B, PKB) pathways. Ras/Raf/MAPK pathways primarily regulate cell proliferation and survival. MAPK is a mitogenic signal, and an activated MAPK enters into cell nucleus and activates transcription factors (e.g. Elkl, Etsl, c-Myc, and the like) due to phosphorylation, thereby interfering cell cycle and transformation process, resulting in the formation of tumors. MAPKs also can induce degradation of proteins and substrates, promote cell migration, and maintain tumor growth (cf. Liebmann C., et al., Cell Signal, 2001, 13, 777-785). PI-3K/Akt signal transduction pathways involve cell growth, apoptosis inhibition, invasion, and migration processes, and play an important role same as that of Ras/Raf/MAPK pathways, wherein, Akt transfers into cell nucleus and regulate more transcription factors (e.g., FKHRL1, NF-kB, Bcl-2, and the like) due to phosphorylation, thereby inhibiting the expression of apoptotic genes; Akt also can phosphorylate glycogen synthase kinase-3 (GSK-3) and mammalian target of rapamycin (mTOR), and hence to upregulate Cyclin D, and phosphorylate a series of inhibitory proteins (e.g., 21CIPI and p27KIPI), and lead to a shorten cell cycle, resulting in tumorigenesis (cf. Shaw R. J., et al., Nature, 2006, 441, 424-430). Therefore, the phosphorylation of receptors catalyzed by PTK ultimately promotes cell proliferation, inhibits cell apoptosis, which is directly associated with tumorigenesis.
The known research results have showed that the receptor tyrosine kinases such as Bcr-abl, EGFR, HER and the like are overexpressed in patients suffering from tumors, in particular, the overexpression of the erbB family (e.g., EFGR, HER2, and the like) can be detected in many human cancers, such as non-small cell lung cancer (NSCLC) (cf. Brabender J., et al., Clin Cancer Res, 2001, 7, 1850-1855), leukemia (cf. Jose Ignacio Martin-Suberoac, et al., Cancer Genet Cytogenet, 2001, 127, 174-176), gastrointestinal cancer (cf. Kapitanovic S., et al., Gastroenterology, 2000, 112, 1103-1113; Ross J. S., et al., Cancer Invest, 2001, 19, 554-558), breast cancer (cf. Klijn J. S., et al., Breast Cancer Res Treat, 1994, 29, 73-83), prostatic cancer (cf. Scher H. I., et al., J Natl Cancer Inst, 2000, 92, 1866-1868), ovarian cancer (cf. Hellstrom I., et al., Cancer Res, 2001, 61, 2420-2423), head and neck cancer (cf. Shiga H., et al., Head Neck, 2000, 22, 599-608), and the like. As the expression of receptor tyrosine kinases in more human tumor tissues and relationship between PTK signal pathways and tumors are further deeply researched, this kind of target sites necessarily produce innovations in the treatment regimes for tumors.
There are abnormal signal transduction pathways in a number of tumor cells, for example, the overexpression of the EGFR proteins are usually seen in epidermal cell derived tumors, the overexpression of PDEFR proteins are usually seen in glioma, and overactivation of Bcr-Abl in CML, and the like. As the results wrong regulations of one or more receptors, multiple tumors clinically become more invasive, and thus are closely related to bad prognosis (cf. Ross J. S., et al., Cancer Investigation, 2001, 19, 554-568). In addition to the aforesaid clinical discoveries, many clinical researches demonstrate that the tyrosine kinases in the erbB family are associated with cytometaplasia, that is, one or more erbB receptors are overexpressed in many cell lines, and EFGR or erbB2 proteins are able to transform non-tumor cells when transfected into these cells. Moreover, many preclinical studies show that the activity of one or more erbB receptors is eliminated by using small molecular inhibitors or inhibitory antibodies to induce effect against proliferation (cf. Mendelsohn J., et al., Oncogene, 2000, 19, 6550-6565).
In recent years, it has been focused on inhibition of the cell signal transduction pathways to develop novel targeted anti-tumor drugs. Singal transduction inhibitors promote cell apoptosis by downregulation of survival and proliferative signals of tumors rather than by cytotoxicity, so that the selectivity is high and toxic side effect is low. At present, there are dozens of signal transduction inhibitors that are clinically applied to treat tumors, and they are mainly tyrosine kinase inhibitors as antitumor drugs, for example, the development of compounds having a structure of 4-(substituted anilino)-quinazoline is advanced for small molecular inhibitors directed against target sites of EGFR tyrosine kinases, such as Gefitinib (Iressa), Erlotinib (Tarceva), Lapatinib, and the like.
Gefitinib is an EGFR tyrosine kinase inhibitor developed by AstraZeneca with a trade name of Iressa, the first EGFR tyrosine kinase inhibitor that is clinically investigated and marketed in Japan in 2002 and in U.S. 2003, and is indicated for the treatment of patients with advanced or metastatic non-small cell lung cancer (NSCLC) who have received prior chemotherapies. Erlotinib is an EGFR tyrosine kinase inhibitor developed by OSI with a trade name of Tarceva, transferred to Genentech and Roche, marketed in America in 2004, and is indicated for the treatment of NSCLC and pancreatic cancer. Erlotinib belongs to the first generation of anilinoquinazoline small molecule inhibitors for the treatment of NSCLC, and is a unique EGFR tyrosine kinase inhibitor that has been confirmed to exhibit survival advantage for advanced NSCLC. Erlotinib is effective for various NSCLC, has a good tolerance, exhibits no myelosuppression and cytotoxicity, and can significantly extends survival and improve quality of life of patients. Lapatinib (with its trade name of Tycerb) is a dual inhibitor of EGFR and HER2 developed by GlaxoSmithKline, and exhibits an inhibitory activity against signal transduction of tumor proliferation and survival higher than a signal receptor inhibitor. Lapatinib was approved by the Food and Drug Administration of America in 2007, and indicated in combination with capecitabine for the treatment of advanced or metastatic breast cancer with overexpression of HER2 and subjected to chemotherapy of such as anthracyclines, taxanes and trastuzumab.
In addition, the published patent applications WO 96/33977, WO 97/30035, WO 98/13354, WO 00/55141, WO 02/41882, WO 03/82290 and EP 837063, all disclose certain quinazoline derivatives substituted with anilino group at 4-position or substituent(s) at 6- and/or 7-position have the inhibitory activity of receptor tyrosine kinases.
Small molecule tyrosine kinase inhibitors as new targeting anticancer drugs open novel window for the treatment and prevention of tumors, and they have slight side effects and good tolerance. Although dozens of small molecule tyrosine kinase inhibitors have made a significant contribution to the clinical treatment of tumors, there is needed to discover additional compounds having better in vivo activity and/or improved pharmacological action than the current tyrosine kinase inhibitors. Therefore, it is of very important significance for the clinical treatment of tumors to develop novel and improved or more effective tyrosine kinase inhibitors, and to deeply investigate the relationship between such new inhibitors and the known target proteins as well as the mechanism of action thereof.